- Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro
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Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroqui
- Ni, Yong,Liao, Jinbiao,Qian, Zhenlong,Wu, Chunxiu,Zhang, Xiangyu,Zhang, Ji,Xie, Youhua,Jiang, Sheng
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- An asymmetric synthesis method of optically pure (R)/(S)-hydroxychloroquine side chains
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The present invention provides an optically pure (R)/ (S) - hydroxychloroquine synthesis method, using a splitting reagent to (±) -2- [(4-aminopentyl)ethylamine] ethanol is split, and recrystallization purification, purified to give optically pure (R) / (S)-2- [(4-aminopentyl) ethylamine] ethanol, the resulting single configuration of hydroxychloroquine side chain and 4,7-dichloroquinoline reaction directly to obtain a single configuration of hydroxychloroquine sulfate. The method has a simple route, easy to obtain raw materials, high yield, good three-dimensional selectivity (ee% >99%), simple operation and green environmental protection, suitable for large-scale scale production.
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- CRYSTALS OF HYDROXYCHLOROQUINE SULFATE
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Two crystals of (S)-(+)-hydroxychloroquine sulfate. One crystal features diffraction peaks at 12.3±0.1°, 13.1±0.1°, 17.9±0.1°, 22.8±0.1°, 23.4±0.1°, 25.1±0.1°, and 26.3±0.1° as 2θ angles in a powder X-ray diffraction pattern. The other crystal features diffraction peaks at 12.8±0.1°, 14.5±0.1°, 16.7±0.1°, 17.6±0.1°, 20.2±0.1°, 21.4±0.1°, 23.8±0.1°, 25.7±0.1°, and 26.0±0.1° as 2θ angles in a powder X-ray diffraction pattern. Also disclosed are methods of preparing crystals of (S)-(+)-hydroxychloroquine sulfate.
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Paragraph 0054
(2021/10/22)
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- TREATMENT OR PREVENTION OF CORONAVIRIDAE INFECTION
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A method of treating or preventing a Coronaviridae infection in a subject comprising administrating a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof to the subject in need thereof, wherein R1 is OH or H, and the Coronaviridae comprises at least one selected from 2019-nCov virus, HCov 229E virus, SARS virus, MERS virus.
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- Medicine for Covid-19 and treatment
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The invention concerns a medicine and a prophylactic medicine for COVID-19 disease. The inventive medicine targets the endosomic, non-endosomic and/or intracellular viral pathways and inhibits them. The best mode of the invention is considered to be the medicine that blocks all three viral pathways. In the best mode the individual dose of a constituent component of the medicine is arranged to a dosage size sufficient to inhibit its designated SARS-CoV-2 viral pathway. This allows the dose of a particular pharmacological agent to be smaller than in a drug with just one kind of pharmacological agent. The best mode of the invention shuts the two cell membrane viral pathways and the one intracellular viral pathway with the minimum efficient dose, thereby preventing drug overdose, and enabling prophylactic or preventive use.
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- Preparation method of hydroxychloroquine
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The invention relates to a preparation method of hydroxychloroquine, which comprises the following steps: protecting hydroxyl of 5-(N-ethyl-N-ethoxyl)-2-aminopentane through a silanization reagent, removing amino protons from tetrahydrofuran or toluene by using a bis(trimethylsilyl lithium amide) solution to form amino anions, and carrying out a substitution reaction with 4.7 dichloroquinoline to generate hydroxychloroquine. The hydroxychloroquine and sulfuric acid are salified in an alcoholic solution to generate hydroxychloroquine sulfate, and the hydroxychloroquine sulfate preparation method provided by the invention has the characteristics of low toxicity, low pollution, high purity, low reaction temperature, short reaction time, high yield and the like, and is suitable for industrialization.
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- Hydroxychloroquine sulfate crystal form B and preparation method thereof
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The invention belongs to the technical field of medicinal chemistry, and particularly relates to a hydroxychloroquine sulfate crystal form B and a preparation method thereof, and XRD and DSC are usedfor characterization. The hydroxychloroquine sulfate crystal form B provided by the invention is simple in preparation method, low in hygroscopicity, good in stability, capable of forming a regular crystal form and higher in solubility, thereby being beneficial to process treatment of medicines, improvement of physical and chemical properties and improvement of patent medicine properties.
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Paragraph 0035-0036
(2021/03/13)
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- Hydroxychloroquine sulfate and preparation method thereof
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The invention discloses hydroxychloroquine sulfate and a preparation method thereof, and relates to the technical field of medicinal chemistry. The preparation method comprises the steps of mixing 4, 7-dichloroquinoline with a hydroxychloroquine side chain, carrying out heating condensation in the presence of an organic base catalyst, adding water and liquid, and carrying out cooling crystallization to obtain hydroxychloroquine; and dissolving hydroxychloroquine in an ethyl acetate and ethanol aqueous solution, heating, dissolving and clarifying, dropwise adding concentrated sulfuric acid, cooling, crystallizing, filtering and drying to obtain hydroxychloroquine sulfate. The method has the beneficial effects that a solvent-free reaction is used, and a catalyst is added, so that high pollution is avoided, the reaction process is accelerated, and the operation is simple; and meanwhile, the HPLC purity of the obtained hydroxychloroquine refined product is not less than 96.50%, the maximum single impurity content is less than 0.10%, the yield can reach 85%, the HPLC purity of hydroxychloroquine sulfate is not less than 98.00%, the maximum single impurity content is less than 0.10%, and the yield can reach 90%.
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Paragraph 0039; 0042-0044; 0047-0049; 0052-0054; ...
(2021/07/31)
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- Preparation method of hydroxychloroquine sulfate
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The invention provides a preparation method of hydroxychloroquine sulfate, specifically a preparation method of hydroxychloroquine sulfate. The method comprises the following steps: (1) preparation of hydroxychloroquine: (1.1) in a first solvent, in the presence of KI and an antioxidant, reacting 4, 7-dichloroquinoline (formula I) with an amino side chain as shown in a formula II to obtain a reaction mixture containing hydroxychloroquine (formula III); and (1.2) separating the hydroxychloroquine from the reaction mixture containing the hydroxychloroquine; and (2) preparation of hydroxychloroquine sulfate: (2.1) in a second inert solvent, reacting the hydroxychloroquine obtained in the step (1) with sulfuric acid to form a salt so as to obtain the hydroxychloroquine sulfate (formula IV).
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Paragraph 0099; 0151; 0159-0164; 0165; 0173-0178; 0179; ...
(2021/07/08)
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- Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof
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The invention belongs to the field of drug synthesis, and discloses a compound with a structure as shown in a formula I (See the specification) and pharmaceutically acceptable salt, tautomer, polymorphic substance, isomer and solvate thereof. Secondly, the invention discloses a method for preparing chiral chloroquine and hydroxychloroquine through chiral high performance liquid chromatography. Finally, the invention discloses application of chiral chloroquine, hydroxychloroquine and salt derivatives thereof in preparation of drugs for treating novel coronavirus pneumonia.
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Paragraph 0186; 0191-0192
(2020/09/16)
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- Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity
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The invention discloses an application of chiral chloroquine, hydroxychloroquine or pharmaceutically acceptable salts of the chiral chloroquine and hydroxychloroquine in preparation of drugs used forpreventing and/or treating coronavirus pneumonia by using a coronavirus key drug target 3CL hydrolase (Mpro) as an action target. The chiral chloroquine and hydroxychloroquine have high bonding strength with the Mpro causing inflammation of the lung and the like; the activity of the Mpro can be significantly inhibited; and the chiral chloroquine and hydroxychloroquine are indicated to have the effect of preventing and treating pneumonia caused by coronaviruses and be able to be used as anti-pneumonia drugs. Through evaluation on the inhibitory activity of an hERG potassium ion channel, the concentration at which the chloroquine, hydroxychloroquine and enantiomers of the chloroquine and hydroxychloroquine are likely to generate cardiotoxicity to the hERG potassium ion channel is provided. The chiral chloroquine and hydroxychloroquine are prepared through chiral high-performance liquid chromatography and chiral synthesis; S-configuration chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine can be selected as a drug independently, or form a pharmaceutical composition for treating diseases caused by the coronaviruses; and due to higher activity and low cardiotoxicity of the chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine, the administration dosage range is greatly widened.
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- Hydroxychloroquine sulfate as well as crystal form and preparation method of enantiomer of hydroxychloroquine sulfate
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The invention relates to hydroxychloroquine sulfate as well as a crystal form and a preparation method of an enantiomer of hydroxychloroquine sulfate. The invention provides a crystal form A hydroxychloroquine sulfate. An X-ray powder diffraction pattern of the crystal form A hydroxychloroquine sulfate has characteristic peaks at 10.8 degrees, 13.0 degrees, 13.3 degrees, 16.9 degrees, 17.2 degrees, 17.5 degrees, 19.9 degrees, 21.3 degrees, 23.5 degrees, 24.0 degrees and 26.7 degrees +/-0.2 degrees, and does not contain hydroxychloroquine nitrogen oxide; the invention provides a hydroxychloroquine crystal, the X-ray powder diffraction pattern has characteristic peaks at 7.5 degrees, 14.9 degrees, 16.5 degrees, 19.2 degrees, 19.6 degrees, 22.8 degrees, 23.6 degrees and 26.7 degrees+/-0.2 degree; the invention provides an S-hydroxychloroquine sulfate monohydrate, the X-ray powder diffraction pattern has characteristic peaks at 12.2 degrees, 13.0 degrees, 14.9 degrees, 17.8 degrees, 22.7 degrees, 23.3 degrees, 25.0 degrees and 26.2 degrees +/-0.2 degrees; the invention also provides R-hydroxychloroquine sulfate, the X-ray powder diffraction pattern has characteristic peaks at 12.2 degrees, 13.0 degrees, 14.9 degrees, 17.8 degrees, 22.7 degrees, 23.3 degrees, 25.0 degrees and 26.2 degrees +/-0.2 degrees.
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Paragraph 0038 ; 0040; 0042
(2020/11/09)
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- Purification method of hydroxychloroquine sulfate
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The invention discloses a purification method of hydroxychloroquine sulfate, which comprises the following steps: (1) dissolving a hydroxychloroquine sulfate crude product in water or a mixed solventof water and a first solvent to obtain a mixed solution I; (2) adding a second solvent into the mixed solution I, and carrying out reflux crystallization; and (3) cooling the reaction product, and filtering and drying the reaction product to obtain a fine hydroxychloroquine sulfate product. The method is excellent in purification effect, so that hydroxychloroquine sulfate with the purity of 99.5%or above and the particle size Dx (90) larger than or equal to 200 microns is prepared. The method is easy and convenient to operate, low in cost, safe, environmentally friendly and suitable for large-scale production.
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Paragraph 0068-0070
(2020/07/24)
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- Preparation method of hydroxychloroquine sulfate
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The invention relates to a preparation method of hydroxychloroquine sulfate, and belongs to the technical field of medicine synthesis. According to the preparation method of hydroxychloroquine sulfate, 7-chloro-4-fluoroquinoline and 5-(N-ethyl-N-2-hydroxyethyl amine)-2-pentylamine are subjected to a reaction to prepare hydroxychloroquine, and then hydroxychloroquine and sulfuric acid are salifiedto prepare hydroxychloroquine sulfate. The 7-chloro-4-fluoroquinoline is prepared from 4,7-dichloroquinoline through a halogen exchange reaction. The preparation method of hydroxychloroquine sulfate has the advantages of low reaction temperature, short reaction time, fewer byproducts, simple technique and favorable reproducibility, and is beneficial to industrial production.
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- Industrial preparation method of hydroxychloroquine sulfate with high purity and high yield
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The invention discloses an industrial preparation method of hydroxychloroquine sulfate with high purity and high yield. The method is mild in reaction condition, an alcohol organic solvent is adopted,reaction is carried out at the temperature of 80-100 DEG C, the reaction temperature is not higher than 100 DEG C, nitrogen protection is not needed, the method is suitable for industrial production,the yield of hydroxychloroquine prepared through the method is larger than or equal to 85%, the purity of hydroxychloroquine is larger than or equal to 99.70%, and the maximum single impurity is smaller than 0.10%. The prepared hydroxychloroquine can be further salified, the purity of the prepared salt is greater than or equal to 99.8%, and the maximum single impurity is less than 0.1%.
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Paragraph 0016-0018
(2020/09/12)
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- A preparation method of the sulfuric acid hydroxy chloroquine
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The invention discloses a high purity sulfuric acid hydroxy chloroquine preparation method. The method to the 4, 7 - dichloro quinolinic and hydroxychloroqine side chain as raw materials for directly preparing hydrochloride hydroxychloroqine, then neutralized sodium alcoholate or polysiloxane, filtering the concentrated, beating, crystallization results in the hydroxy chloroquine is collapsed, finally a certain proportion of the pure water solution with sulfuric acid to form the salt obtained by the reaction of sulfuric acid hydroxy chloroquine. The method for production chloroquine process avoids the phenol or its use of the catalyst, the post-processing also avoids the extraction operation, high purity of the product, in the production process the basic waste water is not generated. The invention has simple operation, high yield, make sulfuric acid hydroxy chloroquine HPLC purity of ≥ 99.6%, the largest single impurity ≤ 0.1%, is more suitable for industrial production.
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- New preparation method of the sulfuric acid hydroxy chloroquine
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This invention relates to a preparation method of the sulfuric acid hydroxy chloroquine, characterized in that in order to mother nucleus of 4, 7 - dichloro quinolinic as the starting material, with the hydroxychloroqine side chain 5 - (N - ethyl - N - 2 - hydroxy serotonin reuptake) - 2 - pentylamine in presence of catalyst, condensation reaction to obtain hydroxychloroqine free base, with the sulfuric acid to form the salt obtained after the sulfuric acid hydroxy chloroquine. This invention has overcome the disadvantages of the prior art, a bit lies in: reduces the consumption of the side chain, the total yield ≥ 90%, sulfuric acid hydroxy chloroquine yield ≥ 96%, overall yield ≥ 86%, sulfuric acid hydroxy chloroquine purity is greater than 99.7%, [...] less than 0.1%, in accordance with the Pharmacopoeia requirements, reaction time is short, simple and convenient operation, pollution is small, low cost, and is suitable for industrial production.
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Paragraph 0003
(2019/03/28)
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- Hydroxychloroquine sulfate crystal form A and preparation method thereof
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The invention discloses a hydroxychloroquine sulfate crystal form A and a preparation method thereof and uses means of XRPD, DSC and IR for representation. The hydroxychloroquine sulfate crystal formA provided by the invention improves the chemical stability of hydroxychloroquine sulfate, is simple in preparation method and easy in industrialized production and can provide a study foundation to development of more hydroxychloroquine sulfate dosage forms at the same time. In the preparation method provided by the invention, a sulfuric acid aqueous solution with the mass percentage being 40-60percent is used, the safety and the operability are improved, and the heat release risk generated by using concentrated sulfuric acid is effectively lowered.
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Paragraph 0046; 0047; 0052
(2018/11/22)
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- Preparing and refining method for hydroxychloroquine and preparation method for sulfate of hydroxychloroquine
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The invention discloses a preparing and refining method for hydroxychloroquine and a preparation method for a sulfate of the hydroxychloroquine. The refining method for the hydroxychloroquine comprises the following steps: performing crystallization on a crude product of the hydroxychloroquine in a mixed solvent of a ketone solvent and an ester solvent to obtain a refined product of the hydroxychloroquine, wherein a content of the hydroxychloroquine in the crude product of the hydroxychloroquine is higher than 92%. According to the method disclosed by the invention, purity of the refined product of the hydroxychloroquine prepared by the method can reach 99.9%, a maximum content of a single impurity is controlled within 0.06%, and a total content of other impurities is lower than 0.04%; andpurity of the hydroxychloroquine sulfate prepared from the hydroxychloroquine can reach 99.8%, and a maximum content of a single impurity is controlled within 0.06%.
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Page/Page column 8-10
(2018/11/03)
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- Preparation method of hydroxychloroquine and sulfate thereof
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The invention discloses a preparation method of hydroxychloroquine and sulfate thereof. The preparation method of the hydroxychloroquine comprises the following steps of step (1), under the inert gasprotection atmosphere, enabling 4,7-dichloroquine and hydroxychloroquine side chain compounds to react at the temperature of 134 to 144 DEG C until the content of 4,7-dichloroquine is smaller than orequal to 10%, so as to obtain a crude product of the hydroxychloroquine, wherein the content of the hydroxychloroquine in the crude product of the hydroxychloroquine is greater than 92%; step (2), recrystallizing the obtained crude product of the hydroxychloroquine in step (1) in a mixed solvent of alcohol solvent and ester solvent, so as to obtain a refined product of the hydroxychloroquine. Thepurity of the refined product of the hydroxychloroquine can reach 99.9%, the maximum content of single impurity is controlled within 0.06%, and the total content of other impurities is smaller than 0.04%.
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Paragraph 0103; 0106-0107; 0108; 0111-0112
(2018/11/04)
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- Side chain, synthesis method thereof, and method for synthesizing hydroxychloroquine sulfate from side chain
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The invention discloses a side chain, a synthesis method thereof, and a method for synthesizing hydroxychloroquine sulfate from the side chain. The synthesis method of the side chain comprises the following steps: 1, condensing N-ethylethanolamine and 5-chloro-2-pentanone to obtain a condensation product; 2, esterifying the condensation product and an acetyl reagent to obtain an esterification product; 3, reducing the esterification product to obtain a reduction product; and 4, reacting the reduction product with a halogenating agent to obtain the side chain. The synthesis method of the hydroxychloroquine sulfate comprises the following steps: 1, reacting 4-amino-7-chloroquinoline with paratoluensulfonyl chloride to obtain 4-Tos-amino-7-chloroquinoline; 2, reacting the side chain with the 4-Tos-amino-7-chloroquinoline to obtain a hydroxyquine base; and 3, reacting the hydroxyquine base with sulfuric acid to obtain the hydroxychloroquine sulfate. The synthesis method of the new side chain avoids the ammonification process and the catalytic hydrogenation process, and is safe and environmentally friendly, and the hydroxychloroquine sulfate can be obtained through low-temperature condensation of the side chain, so the quality of the above products is remarkably improved, and the production flow is simplified.
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Paragraph 0091; 0132; 0137; 0138; 0142; 0147
(2018/01/04)
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- A method for preparing sulfuric acid hydroxy chloroquine
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The invention discloses a preparation method of hydroxychloroquine sulfate. The preparation method is characterized by comprising the following steps: condensing 4,7-dichloroquinoline serving as an initial raw material and a hydroxychloroquine side chain under the action of a catalyst, so as to obtain hydroxychloroquine; and reacting hydroxychloroquine with sulfuric acid, so as to prepare the hydroxychloroquine sulfate. According to the method disclosed by the invention, the defects in the prior art are overcome. The method has the advantages that the yield of the prepared hydroxychloroquine sulfate crude product is greater than or equal to 85%, the yield of hydroxychloroquine sulfate is greater than or equal to 94%; the total yield is greater than or equal to 80%; the purity of the prepared hydroxychloroquine sulfate HPLC is greater than or equal to 99.6%; the maximum single impurity is smaller than 0.1%; the method accords with the requirements of United States pharmacopeia, is short in reaction step, and simple in the whole technological operation; and the obtained product is high in quality, high in yield, and relatively suitable for industrial production.
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Paragraph 0036; 0037; 0043-0046; 0050; 0051; 0057-0065
(2018/11/03)
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- A sulfuric acid hydroxy chloroquinoline industrial preparation method
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The invention provides an industrial production method for hydroxychloroquine sulfate, which includes the following steps: enabling 4.7-dichloroquinoxaline and 5-(N-ethyl-N-ethoxyl)-2-amino pentane to react under gas shield for 13-24 h at a gradually increased temperature of 120-130 DEG C to obtain hydroxychloroquine; preparing the hydroxychloroquine sulfate after the reaction between the hydroxychloroquine and an alcohol sulfate solution at the temperature of 20-30 DEG C. According to the method, the yield of the obtained crude product of the hydroxychloroquine is not smaller than 85%, the yield of the obtained hydroxychloroquine sulfate is not smaller than 85%, the yield of the obtained hydroxychloroquine sulfate HPLC is not smaller than 99.5%, the yield of single impurity is not larger than 0.1%, so that requirements of United States Pharmacopeia is met; the novel method is simple in procedure, is environment-friendly and easy in industrial production.
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Paragraph 0017; 0041-0046
(2018/07/10)
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